Declines in the mass and strength of skeletal muscle lead to decrements in functional abilities of older adults. In fact, muscle weakness is the central component of the multisystem syndrome of frailty--a strong predictor of disability, illness and even death. While this decline is universal in occurrence, the age of onset and speed of progression are quite variable, with some persons becoming frail and disabled in their 70s as a result of these changes, yet some remaining quite robust into their 10th decade. There is now evidence to support our hypothesis that such variability is due, in part, to genetic heterogeneity and to associated gene-environment interactions; i.e. there are polymorphisms that will most always protect against development of frailty, some that will hasten it, and some that will have effects apparent only in a certain hormonal or nutritional milieu. Gene variants that modulate the rate of decline in strength will clearly identify molecular paths important to that decline, paths perhaps important to development of frailty more generally, or even to the aging process itself. We propose a screen for genetic contributors to heterogeneity in the rate of decline in strength with aging. An expert panel will prioritize genes based upon likelihood of contribution to the molecular pathway of a known predictor of decline in strength in epidemiologic studies (e.g. IL6, DHEAS). Haplotype analysis will be performed on approximately 200 genes, using bead array technology to assay 1,500 SNPs. Genotyping will be performed on DNA of 1,012 older women of longitudinal studies specifically designed to assess contributors to functional decline and disability (Women's Health and Aging Studies I and II). Individual SNPs or haplotypes that associate with longitudinal rate of decline in strength, individually or in interaction with a serum biomarker (e.g. IL6 receptor gene X serum IL6), will be genotyped in a second longitudinal cohort of older adults (Cardiovascular Health Study). Genomic regions thereby confirmed to associate with decline in strength will be sequenced to identify specific variants accounting for the associations. Identifying molecular pathways in which variation predicts declines in strength will aid in risk stratification for clinical and research endeavors, development of new therapies, and identification of new targets for basic research on age-related changes in body composition, resultant frailty, and even the aging process itself.